In general, the treatment of non-insulin-dependent diabetes mellitus (NIDDM) involves a combination of alimentotherapy, kinesitherapy, and administration of insulin or orally active hypoglycemic agents. As the oral hypoglycemic agents, there are currently known sulfonylureas such as tolbutamide, chlorpropamide, acetohexamide, glibenclamide and tolazamide, and biguanides such as phenformin, buformin and metformin.
While the sulfonylureas have strong hypoglycemic action, they sometimes induce severe and prolonged hypoglycemia, and chronic use thereof may impair their effectiveness. In addition, the biguanides frequently induce severe lactic acidosis. For these reasons, the use of these medications has required considerable amount of attention.
Meanwhile, Japanese Patent Unexamined Publication No. 85372/1986 discloses that thiazolidinedione derivatives, such as 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione , have hypoglycemic action.
Japanese Patent Unexamined Publication No. 170478/1991 teaches that oxazolidinedione derivatives, such as 5-[4-[2-(2-phenyl-5-methyloxazol-4-yl)ethoxy]benzyl]-2,4-oxazolidinedione, have hypoglycemic action and hypocholesterolemic action, and Japanese Patent Unexamined Publication No. 165735/1995 teaches that oxazolidinedione derivatives, such as 5-[3-[4-[(2-benzo[b]thien-2-yl-5-methyl-4-oxazolyl)methoxy]phenyl]propyl]- 2,4-oxazolidinedione, also have hypoglycemic action and hypocholesterolemic action.
Japanese Patent Application under PCT laid-open under Kohyo No. 5-507920 discloses that 3-aryl-2-hydroxypropionic acid derivatives, such as .alpha.-methoxy-4-[2-(5-methyl-2-phenyl-4-phenyl-4-oxazolyl)ethoxy]benzene propanic acid and ethyl .alpha.-acetylthio-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzenepropio nate, have hypoglycemic action. This publication also recites ethyl .alpha.-hydroxy-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzenepropanate as an intermediate compound. In addition, Japanese Patent Application under PCT laid-open under Kohyo No. 5-508654 discloses that hydroxyurea derivatives, such as N-[(methoxycarbonyl)oxy]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phe nyl]methyl]urea, have hypoglycemic action.
WO95/18125 discloses that isoxazolidinedione derivatives, such as 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxazolidinedion e, have hypoglycemic action.
WO94/13650 discloses that dimethyl 2-[4-[2-[N-(2-benzooxazolyl)-N-methylamino]ethoxy]phenylmethyl]propane-1,3 -dioate and dimethyl 2-[4-[2-[N-(2-benzooxazolyl)-N-methylamino]ethoxy]phenylmethylene]propane- 1,3-dioate have hypoglycemic action.
Japanese Patent Unexamined Publication No. 53555/1995 recites ethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate as an intermediate compound.
Japanese Patent Unexamined Publication No. 101945/1995 describes ethyl (E)-4-[2-(5-ethyl-2-pyridyl)ethoxy]cinnamate as a reference compound.
The above-mentioned compounds do not necessarily show satisfactory activities. Rather, the use of these compounds gives rise to concerns about the side effects such as toxicity. Moreover, the above-mentioned literatures do not suggest a propionic acid derivative such as the compounds of the present invention.
Further, WO95/18125 discloses diesters of malonic acid, such as dimethyl 4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzilidenemalonate, as an intermediate compound for isoxazolidinedione derivatives such as 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxazolidinedion e. Nevertheless, it does not suggest that such diesters of malonic acid have hypoglycemic action, much less gives any data suggesting the hypoglycemic action.